This invention relates to a method of inhibiting retroviruses such as human immunodeficiency virus (HIV). More particularly, the invention concerns a method for providing enhanced antiviral activity with N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol (deoxynojirimycin) which have potential use for the treatment of acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC).
Acquired immune deficiency syndrome, which only a few years ago was a medical curiosity, is now a serious disease. As a consequence, a great effort is being made to develop drugs and vaccines to combat AIDS. The AIDS virus, first identified in 1983, has been described by several names. It is the third known T-lymphocyte virus (HTLV-III) and has the capacity to replicate within cells of the immune system and thereby lead to a profound destruction of T4.sup.30 T-cells (or CD4.sup.30 cells) See, e.g., Gallo et al., Science 224, 500-503 (1984), and Popovic et al., Ibid., 224, 497-500 (1984). This retrovirus had been known as lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) and, most recently, as human immunodeficiency virus (HIV). Two distinct AIDS viruses, HIV-1 and HIV-2, have been described. HIV-1 is the virus originally identified in 1983 by Montagnier and co-workers at the Pasteur Institute in Paris [Ann. Virol. Inst. Pasteur 135 E, 119-134 (1984)], while HIV-2 was more recently isolated by Montagnier and his coworkers in 1986 [Nature 326, 662 (1987)]. As used herein these viruses in a generic sense.
Although the molecular biology of AIDS is beginning to be unraveled and defined, much more needs to be learned and understood about this disease. In the meantime, numerous approaches are being investigated in the search for potential anti-AIDS drugs and vaccines. Development of an AIDS vaccine is hampered by lack of understanding of mechanisms of protective immunity against HIV, the magnitude of genetic variation of the virus, and the lack of effective animal models for HIV infection. See, for example, Koff and Hoth, Science 241, 426-432 (1988).
The first drug to be approved by the U.S. Food and Drug Administration (FDA) for treatment of AIDS was zidovudine, better known under its former name azidothymidine (AZT). Chemically, this drug is 3'-azido-3'-deoxythymidine. This drug was originally selected as a potential weapon against AIDS because it was shown to inhibit replication of the virus in vitro. Such in vitro tests are useful and virtually the only practical method of initially screening and testing potential anti-AIDS drugs. A serious drawback of AZT, however, is its toxic side-effects. Thus, the search for better anti-AIDS drugs continues.
More recently, certain glycosidase inhibitors have been tested for activity against the AIDS virus. Three such compounds suggested as potential anti-AIDS drugs are castanospermine, 1-deoxynojirimycin (DNJ) and 2,5-dihydroxymethyl-3,4-dihydroxy-pyrrolidine (DMDP). See, e.g., Sunkara et al., Biochem. Biophys. Res. Commun. 148(1), 206-210 (1987); Tyms et al., Lancet, Oct. 31, 1987, pp. 1025-1026; Walker et al., Proc. Natl. Acad. Sci. USA 84, 8120-8124(1987); ##STR1## Thus, castanospermine, which is an alkaloid isolated from the seeds of the Australian chestnut tree, has been found to interfere with normal glycosylation of HIV virions, thereby altering the envelope glycoprotein and preventing entry of HIV into target cells. However, only a modest reduction in virion infectivity was found.
In PCT Inter. Appln. WO 87/03903, published July 2, 1987, the N-methyl derivative of deoxynojirimycin (DNJ) also was disclosed as having activity against HIV ostensibly based on its glucosidase I inhibitory activity. However, it was subsequently shown by Fleet et al., FEBS Lett. 237, 128-132 (1988), that not all glucosidase I inhibitors are effective inhibitors of HIV. Therefore, some other mechanism may be responsible for HIV inhibitory activity. For example, while the known inhibition of the cytopathic effect (CPE) by the o-glucosidase I inhibitor castanospermine is confirmed, neither the epimer L-1,6-diepicastanospermine nor the stereoisomer of castanospermine, L-6-epicastanospermine, were found to be inhibitory.
So also, although both enantiomers of 1,4-dideoxy-1,4-imino-arabinitol are known glucosidase inhibitors [Fleet et al., Tetrahedron Lett. 26, 3127-3130 (1985); Fleet et al., Chemistry Lett., 1051-1054 (1986)], the L-enantiomer has strong HIV inhibitory activity whereas the D-enantiomer has very little effect on HIV replication. For both enantiomers, N-methylation reduced rather than increased anti-HIV activity. Neither the azofuranose analog of glucose nor the N-benzyl derivative were found to have an effect on CPE. Similarly, no HIV inhibition was observed for fagomine, the 2-deoxyglucose analog, although it too is known to have .alpha.-glycosidase inhibitory activity. See Fleet et al., FEBS Lett. 237, 128-132 (1988).
Karpas, et al., Proc. Natl. Acad. Sci. USA 85, 9229-9233 (1988), report that whereas the N-methyl- and N-ethyl-DNJ reduce the yield of infectious HIV by an order of four and three logarithms, respectively, the N-butyl-DNJ reduces infectious viral particles by a logarithmic order greater than five at nontoxic concentrations. See also U.S. Pat. No. 4,849,430 on the antiviral use of N-butyl-DNJ.